Structure‐based design, synthesis, and evaluation of Bcl‐2/Mcl‐1 dual inhibitors

Abstract

Based on our previously reported Bcl-2/Mcl-1 dual inhibitor 4-thiomorpholinyl-2-cyano-3-amidinophenalenone (A1) that simultaneously occupies the p2 and p4 hydrophobic pockets of Bcl-2 and Mcl-1, we optimized molecules with different bond angles of the groups extending to the p4 pocket and bulky hydrophobic groups to explore p2. Research on structure-activity relationship resulted in a new derivative B4 that is capable of occupying both the p2 and p4 more deeply and completely than A1, with K i values determined by fluorescence polarization assay (FPAs) improving to 0.31 μM for Bcl-2 and 0.16 μM for Mcl-1. Furthermore, B4 exhibited selective lethality on cancer cells over normal cells. It showed stronger apoptosis induction than (-)-gossypol on a Bcl-2/Mcl-1-dependent cancer cell line and killed an Mcl-1-dependent cell line which is resistant to ABT-199 treatment. K E Y W O R D S anticancer activities, apoptosis, Bcl-2/Mcl-1 dual inhibitor

Inhibition of Anti-Apoptotic Bcl-2 Proteins in Preclinical and Clinical Studies: Current Overview in Cancer

“…Single agent antitumor activity of S1, the BH3-mimetic dual inhibitor of Bcl-2 and Mcl-1, and its derivative B4, has been also reported in cancer models with different origin [117].…”

Mixture-Based Screening of Focused Combinatorial Libraries by NMR: Application to the Antiapoptotic Protein hMcl-1

“…The obtained pose is reasonable as it positions the agent’s P1 and P4 moieties in two adjacent hydrophobic pockets, while the Asp acid is engaged in a salt bridge with Arg 263, hence binding in a typical fashion as reported for other BH3 mimetics (Figure ). ,− …”

Another structural correction for 1‐oxo‐1H‐phenalene‐2,3‐dicarbonitriles: Synthesis of a potent BCL‐2 inhibiting 7‐phenoxy derivative

“…[ 10 ] Moreover, derivatives of A were shown to have different bioactive properties, such as cytotoxicity against tumor cells, [ 7,11 ] DNA intercalation and apoptosis induction, [ 12 ] fibroblast growth factor receptor 1 inhibition, [ 13 ] and inhibition of the B‐cell lymphoma 2 (BCL‐2) family of proteins. [ 14–20 ]…”

“…[10] Moreover, derivatives of A were shown to have different bioactive properties, such as cytotoxicity against tumor cells, [7,11] DNA intercalation and apoptosis induction, [12] fibroblast growth factor receptor 1 inhibition, [13] and inhibition of the B-cell lymphoma 2 (BCL-2) family of proteins. [14][15][16][17][18][19][20] Despite numerous studies describing physicochemical and biological properties of 8-oxo-8H-acenaphtho [1,2-b]pyrrole-9carbonitrile (A) derivatives, it was only in 2013/2014 when the original authors published two separate corrigendum papers, [21,22] in which the core structure A was revised. They used two-dimensional (2D) nuclear magnetic resonance (NMR) techniques to reassign the molecule as 1-oxo-1H-phenalene-2,3-dicarbonitrile (scaffold B, Figure 1).…”

“…Another contrasting observation in the chemistry of these compounds was the outcome of reacting primary amines for 1-3 h in MeCN with phenalenones that possessed thiol-and secondary amine-based substituents at position 6. Some studies reported substitutions (3.0 equiv amine) to occur at position 6 (Figure 2c), [7,23] whereas others [18,20,28] reported Michael additions (10 equiv amine) to give 3-substituted derivatives in up to 35% yield (Figure 2d) without the nucleophilic substitution at position 6.…”